Foto del docente

Silvia Bordoni

Professoressa associata confermata

Dipartimento di Chimica Industriale "Toso Montanari"

Settore scientifico disciplinare: CHIM/03 CHIMICA GENERALE E INORGANICA

Contenuti utili

Bioactive molecules to Ruthenium coordination

The main aspect of my current research is concerning the “Design of new organometallic complexes, based on Ru-coordinated bioactive species”. In the past ten years, it has been commonly assumed that Ruthenium species replaced as anticancer compound the most popular and commonly used cis-Platinum drug for more effectiveness. In fact, they reveal two main advantageous requisites:

-surmounting the resistance upon longer treatments, that generally affect the common Pt drugs, used generally in the case of severe and drastic conditions.

-limiting the toxic effects towards the intact cells. With this respect, it warrants to underline that base-research investigations on the coordination structures exhibited by newly synthesized Ru-complexes are certainly of primary interest to correlate the structure modulation to the sometimes inexplicable, multifaceted anticancer activity. Firstly, it is worthy to make a premise showing the previous reactions that we studied by applying the strategy of coordinating nucleobases as thymine to the Ru-metal site as an effective approach to promptly obtain novel bioactive molecules. In our case we use a thymine opportunely derivatized by a carboxy tethered function. The choice is founded on the reason that carboxy moiety is exhibited by a great number of biological metals to effectively graph bioenzymes. In our case, the synthesis by using two equivalents of THAcH (tymine acetic acid) revealed a quite sustainable path, due mainly to the observation that the product formation affording a doubly coordinated species simultaneously exhibiting chelate and monohapto-thymine acetates and concomitantly releases solely molecular hydrogen. On the contrary, in the case addition of one THAcH equivalent, a large metallacycle has instead been obtained, showing an heteroleptic, namely mixed (N,O) coordination. It is opportune to underlying that both metal skeleton rigidity and steric encumbrance drives the reactions prevalently towards O-coordination, unless the impeded rotation of one coordinate thymine-acetate about the large phosphine ligands is removed by the cleavage of one Ru-P bond, triggering the reposition to vicinal cis-location of the phosphine ligands. It is remarkable to note that because of the reduced acidity exhibited by the metal centre, the addition of a second ligand is consistently more difficult and commonly requires longer times and higher temperature-solicitated reactions. So, in line with these considerations, in the second attach of acetate-ligand promotes a trans-cis isomerization, which is ruled out by steric reasons. What it is important to know is that the metal anchoring promotes a tautomerization rearrangement from keto-amino to iminol forms. which implies the reposition of the proton atoms towards the rare isomeric forms. This transformation can be designated as a key-point process for interpreting the biological activity, such as cell apoptosis, because of the mismatching in the tween-nucleobase pairing of the DNA. Likewise, in the case of pyrrolyl-carboxy acid ligand, exclusively (O,O) coordinative fashion mode is obtained, in which an equatorial position prevails, parallelly at least to one phenyl Phosphine substituent. The theoretical investigations, made by using Density Functional Calculations suggest the identification of planar stereogeometry for all the possible stable molecular model structures (that means that all exhibit the lower energy as possible), suggesting the occurrence of remarkable intramolecular interactions between the almost parallel aromatic rings such as p-p stacking and also between the acidic pyrrole NH-functions with the pi-cloud of the same phenyl phosphines. Another relevant interaction is observed on the other side of the molecule by the -CH (hybridized sp2) phenyl substituents which are almost perpendicular with the carbonyl-Ru fragment. These short-range intramolecular interactions, evaluated by comparison with the sum of Van der Waals radii result globally 18, and all together are responsible to determine the most stable thermodynamic structures. It is worthy to recall that the diastereomers are defined by the reciprocal location of Ru-H and Ru-CO functions and the IR shifts of Ru-carbonyl frequency may be considered as a probe for the reaction trend and. On the other hand, the hydride NMR resonances, designated by very high-shifted signals constitutes a convincing evidence of the number of isomeric species obtained. New perspectives imply the adoption of immuno-modulator ligands as asparagine or 5-HTP 5-hydroxytriptophane molecule as serotonin promoter, to study the benign synergistic effects of the natural molecules with the stabilizing action of Ru metal site viewed as carrier centre and mediator towards the living fragments as DNA. Many chemical features, as stability and solubility in very polar media, by simulating the plasma liquid mainly composed by water, should further be studied to achieve a potential response towards anticancer activity. Many biological responses towards specific tumoral cellular lines are still to be claimed by in-vitro and in-vivo trials. Long prospecting way is to be expected to achieve an auspicable pharmaceutical drug remedy… but any plausible single path woths to be under-stepped, to not leave unattended any novel strategies to cope and solve the common enemy for the entire living population.